Whereas macrocyclic chemistry, in general, is highly developed, the art of manufacturing cross-bridged macrocycles is new. Certain such macrocycles, such as cross-bridged derivatives of cyclam, have only recently been synthesized in small amounts, and commercial processes are not known. It would be highly desirable to have such processes, since cross-bridged macrocycles have unique advantages as proton sponges or when used as ligands in the catalysis of bleaching.
Macrocycles have been made in numerous ways. See, for example, "Heterocyclic compounds: Aza-crown macrocycles", J. S. Bradshaw et al., Wiley-Interscience, 1993, which also describes a number of synthesis of such ligands. Though macrocycle synthesis is well developed in general, synthesis of cross-bridged macrocycles is not. Cross-bridged macrocycle synthesis is rare and difficult, and involves multiple steps and unpleasant solvents (DMF, acetonitrile, or the like).
Cross-bridging, i.e., bridging across nonadjacent nitrogens, of a known macrocycle, cyclam (1,4,8,11-tetraazacyclotetradecane), is known in limited context. It is, for example, described by Weisman et al, J. Amer. Chem. Soc., (1990), 112(23), 8604-8605. More particularly, Weisman et al., Chem. Commun., (1996), pp. 947-948, describe a range of assertedly new cross-bridged tetraamine ligands which are bicyclo[6.6.2], [6.5.2], and [5.5.2] systems, and their complexation to Cu(II) and Ni(II), demonstrating that the ligands coordinate the metals in a cleft. Specific complexes reported include those of the ligands 1.1: ##STR1##
in which A is hydrogen or benzyl and (a) m=n=1, or (b) m=1 and n=0; or (c) m=n=0, including a Cu(II)chloride complex of the ligand having A=H and m=n=1; Cu(II) perchlorate complexes where A=H and m=n=1 or m=n=0; a Cu(II)chloride complex of the ligand having A=benzyl and m=n=0; and a Ni(II)bromide complex of the ligand having A=H and m=n=1. This handful of complexes appears to be the total of those known wherein the bridging is not across "adjacent" nitrogens.
Weisman also provides a synthesis method for a cross-bridged cyclam which uses three steps, two of which are acetonitrile as solvent. These steps are (1) reaction of a parent macrocycle with glyoxal to form a bisaminal and (2) quaternization of the bisaminal with methyl iodide, to form a dimethylated bisaminal diiodide. A further step, (3), reduction of the diquaternary intermediate produced in the second step, is required to make the desired product. This step uses ethanol as solvent. There is an apparent requirement to conduct the synthesis at relatively high dilution, which is commercially unattractive. Yields are borderline for commercial utility (only 80% and 85% in the first and second steps, respectively.) In view of the desirable properties of cross-bridged macrocycles as ligands and the limitations of the existing method of making such a macrocycle, there is a clear need and desire for improvement in the synthesis of such cross-bridged macrocycles.
To summarize, current syntheses have one or more of the following limitations: (a) they use relatively environmentally undesirable solvents, such as acetonitrile; (b) they may incorporate "high-dilution" steps, increasing solvent consumption; (c) they require switching from one solvent to another in different stages of manufacture; increasing cost and complexity further, and (d) they are wasteful in calling for large excesses of materials such as alkyl halides and/or reducing agents.
Accordingly, it would be highly desirable to improve the synthesis of cross-bridged macrocycles, and in particular, methods for making cross-bridged derivatives of cyclam, and to provide methods for synthesizing Mn-containing complexes with cross-bridged macrocyclic ligands. These and other improvements are secured herein, as will be seen from the following disclosure.